Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01–65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration.


Implemented disability scores
The Expanded Disability Status Scale (EDSS) 1 is a widely accepted method to quantify disability related to Multiple Sclerosis on an ordinal scale ranging from 0 (no neurological signs) to 10 (death due to Multiple Sclerosis).It's calculated by separate evaluation of the following seven Functional Systems (FS) and ambulation: visual, brainstem, pyramidal, cerebral, cerebellar, sensory, and bowel and bladder.Each of the FS is scored on an ordinal clinical rating scale from 0 (no signs) to 5 or 6 (depending on the FS), resulting in a FS score (FSS).Only signs which have not already been present prior to the infection were taken into account.Because the differentiation between new and preexisting symptoms was not unequivocally possible for the visual and bowel and bladder FS, these two scores were not included in the present study.If a single or a combination of FS was not assessable (e.g., ambulation in bedridden patients), all other FS were assessed.
The Modified Rankin Scale 2 is the most widely used clinical outcome measure for stroke patients, measuring the degree of disability after a stroke on an ordinal scale from 0 (no symptoms) to 6 (death).We adapted this score to COVID-19 symptoms.The INCAT disability score 3 measures activity limitation due to disability of the upper and lower limbs and is primarily used in research on inflammatory polyneuropathy.Arm and leg disability are both classified from 0 (no symptoms) to 5.
The Barthel Index 4 completed our test battery as an ordinal measure of performance in ten activities of daily living and mobility.

Calculation of neuropsychological z-scores
In the German norms of the Symbol Digit Modalities Test (SDMT) 5 , the total number of correct digits is transformed into a z-score correcting for age and education.This correction is applied by using a formula of the following format:
Unfortunately, almost half of our participating patients (N=64, 41%) fell outside the range of the highest age category.Subjects older than 59 years old were not considered in the development of this normative formula and therefore, they cannot be assigned to any of the available age groups.To avoid overestimation of cognitive impairment in elderly patients by assigning z-scores based on the highest available age category (50-59 years), we added two categories, inspired by the range of those provided in the German norms: 5=60-69 years, 6=≥70 years.Following the published cut-off-score for the other age groups, slowed information processing speed was defined based on a z-score of ≤ -1.68.
To explore the effect of this adaptation, we analyzed the number of patients classified as impaired using 1) our adapted age categories and 2) four age categories only, assigning all patients older than 50 years to the same category.Six patients were classified as impaired in 2) but not in 1).Total scores of the Montreal Cognitive Assessment (MoCA, version 7) 6 were transformed into z-scores based on German norms, correcting for sex, age, and education. 7No results for the Glasgow coma scale 10  sCV Ulnaris (unsedated):

Supplementary Figure S4 Odds Ratios (95% CI) of mortality excluding patients with diabetes mellitus
This figure shows the odds ratios of mortality (with 95% confidence interval) for the subsample of patients without diabetes mellitus on the log scale.The number of comorbidities was defined according to the extended Charlson comorbidity index. 9 at admission are displayed because all patients achieved the highest possible score.p-values <0.05 are in boldface.CI = confidence interval; adm= score refers to the time of admission to the hospital; MRS = Modified Rankin Scale; WHO score = WHO clinical progression scale; PNS = peripheral nervous system; CNS = central nervous system; NCS = nerve conduction studies; MEP = motor evoked potentials; SSEP = somatosensory evoked potentials; SSR = sympathetic skin response; BR = blink reflex.Supplementary Figure S3 Odds Ratios (95% CI) of mortality based on the raw values in the electrophysiological assessment This figure shows the odds ratios of mortality (with 95% confidence interval) on the log scale, based on the raw values in the electrophysiological assessment.The mean of the left and right sight of the body was used for the N20, P40, CMCT and cortical latency.p-values < .05are in boldface.CI = confidence interval, sCV = sensory nerve conduction velocity, SNAP = sensory nerve action potential, CMAP = compound muscle action potential, mCV = motor nerve conduction velocity, SSR = sympathetic skin response, CMCT = central motor conduction time.
All scores refer to the time of the examination if not indicated otherwise.p-values < .05are in boldface.DM = diabetes mellitus, CI = confidence interval, MRS = Modified Rankin Scale, PNS = peripheral nervous system, NCS = nerve conduction studies, MEP = motor evoked potentials, SSEP = somatosensory evoked potentials, SSR = sympathetic skin response, BR = blink reflex.MRS: 2.58 (

Supplementary Table S5 Normal reference range of the parameters of interest in the somato- sensory evoked potentials
Note: Obtained by assessments of representative healthy controls defining cut-off values >2.5 standard deviations from the means of the controls.

Supplementary Table S6 Odds ratios of mortality after controlling for age and sex (with 95% confidence interval)
All scores refer to the time of examination if not indicated otherwise.Number of comorbidities were defined according to the extended Charlson comorbidity index.